화학공학소재연구정보센터
Journal of Industrial and Engineering Chemistry, Vol.65, 343-348, September, 2018
Natural deep eutectic solvents as a storage medium for human interferon-α2: a green and improved strategy for room-temperature biologics
E-mail:,
The inherent vulnerability of protein biologics to high temperature is the origin of their limited use in clinical settings where proper storage and handling systems are not available. Herein, we demonstrate he first application of natural deep eutectic solvents (NADES) as a temperature-stable storage medium for a real therapeutic protein, human interferon-alpha 2 (IFN-α2). A formulation of IFN-α2 based on a NADES composed of choline chloride and fructose at a 1:1 molar ratio (CCl:Fru) had no influence on the activity of IFN-α2. The NADES provided an appropriate environment for effective protection of IFN-α2 from thermal denaturation at mid (37 °C) and high (70 °C) temperatures during long-term (90 days) and short-term (2 h) storage. Protein stability in the presence of CCl:Fru was demonstrated by orthogonal or complementary methods, including in vitro activity assay, circular dichroism spectroscopy and extrinsic fluorescence spectroscopy. In view of their biocompatibility, customizable properties, and the simplicity of synthesis and use, NADESs are suggested as a green and improved short-term and long-term storage medium that could facilitate the development of room-temperature biologics.
  1. Leader B, Baca QJ, Golan DE, Nat. Rev. Drug Discov., 7, 21 (2008)
  2. Sathish JG, Sethu S, Bielsky MC, de Haan L, French NS, Nat. Rev. Drug Discov., 12, 306 (2013)
  3. Coiffier B, Future Oncol., 13, 1 (2017)
  4. Chung J, Exp. Mol. Med., 49, 1 (2017)
  5. Mandal A, Pal D, Agrahari V, Trinh HM, Joseph M, Mitra AK, Adv. Drug Deliv. Rev., 67 (2018).
  6. Ammann C, AAPS PharmSciTech, 12, 1264 (2011)
  7. Tan LJ, Group SVDW, Vaccine, 32, 2389 (2014)
  8. Cheyne J, Rev. Infect. Dis., 11, S617 (1989)
  9. Wolfson LJ, Gasse F, Lee-Martin SP, Lydon P, Magan A, Tibouti A, Johns B, Hutubessy R, Salama P, Okwo-Bele JM, Bull. World Health Organ., 86, 27 (2008)
  10. Milstien JB, Galazka AM, Kartoglu UM, Zaffran M, Immunization, Vaccines and Biologicals . WHO, WHO/IVB/06.10 (2006).
  11. Parkins DA, Lashmar UT, Pharm. Sci. Technol. Today, 3, 129 (2000)
  12. Wang W, Int. J. Pharm., 185, 129 (1999)
  13. Chi EY, Krishnan S, Randolph TW, Carpenter JF, Pharm. Res., 20, 1325 (2003)
  14. Capelle MA, Gurny R, Arvinte T, Eur. J. Pharm. Biopharm., 65, 131 (2007)
  15. Maa YF, Hsu CC, Int. J. Pharm., 140, 155 (1996)
  16. Griebenow K, Klibanov AM, Proc. Natl. Acad. Sci. U. S. A., 92, 10969 (1995)
  17. Klibanov AM, Nature, 409, 241 (2001)
  18. Dick FD, Occup. Environ. Med., 63, 221 (2006)
  19. Gross G, Terzo SD, Kumar SK, Stabilized interferon alpha solutions, Google Patents (1998).
  20. Yuen PHC, Kline DF, Stable aqueous alfa interferon solution formulations, Google Patents (1999).
  21. Ruiz L, Reyes N, Duany L, Franco A, Aroche K, Rando EH, Int. J. Pharm., 264, 57 (2003)
  22. Zhang J, Pritchard E, Hu X, Valentin T, Panilaitis B, Omenetto FG, Kaplan DL, Proc. Natl. Acad. Sci. U. S. A., 109, 11981 (2012)
  23. Pena-Pereira F, Namiesnik J, ChemSusChem, 1784 (2014).
  24. Dai Y, van Spronsen J, Witkamp GJ, Verpoorte R, Choi YH, Anal. Chim. Acta, 766, 61 (2013)
  25. Dai Y, van Spronsen J, Witkamp GJ, Verpoorte R, Choi YH, J. Nat. Prod., 76, 2162 (2013)
  26. Francisco M, van den Bruinhorst A, Kroon MC, Angew. Chem.-Int. Edit., 52, 3074 (2013)
  27. Mondal D, Sharma M, Mukesh C, Gupta V, Prasad K, Chem. Commun., 49, 9606 (2013)
  28. Zeng Q, Wang YZ, Huang YH, Ding XQ, Chen J, Xu KJ, Analyst, 139, 2565 (2014)
  29. Lores H, Romero V, Costas I, Bendicho C, Lavilla I, Talanta, 162, 453 (2017)
  30. Mbous YP, Hayyan M, Hayyan A, Wong WF, Hashim MA, Looi CY, Biotechnol. Adv., 35, 105 (2017)
  31. Radosevic K, Bubalo MC, Srcek VG, Grgas D, Dragicevic TL, Redovnikovic IR, Ecotoxicol. Environ. Safe, 112, 46 (2015)
  32. Mann JP, McCluskey A, Atkin R, Green Chem., 11, 785 (2009)
  33. Constatinescu D, Herrmann C, Weingartner H, Phys. Chem. Chem. Phys., 12, 156 (2010)
  34. Esquembre R, Sanz JM, Wall JG, del Monte F, Mateo CR, Ferrer ML, Phys. Chem. Chem. Phys., 15, 11248 (2013)
  35. Bayraktar Y, Koseoglu T, Sommer C, Kayhan B, Temizer A, Uzunalimoglu B, DeMaria N, VanThiel DH, J. Viral Hepat., 3, 129 (1996)
  36. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH, Albrecht J, N. Engl. J. Med., 339, 1493 (1998)
  37. Mahon FX, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, et al., Blood, 92, 4059 (1998)
  38. Opravil M, Hirschel B, Bucher HC, Luthy R, Study SHC, Int. J. Std. Aids, 10, 369 (1999)
  39. Gutierrez MC, Ferrer ML, Mateo CR, del Monte F, Langmuir, 25(10), 5509 (2009)
  40. Nam MW, Zhao J, Lee MS, Jeong JH, Lee J, Green Chem., 17, 1718 (2015)
  41. Semisotnov GV, Rodionova NA, Razgulyaev OI, Uversky VN, Gripas AF, Gilmanshin RI, Biopolymers, 31, 119 (1991)
  42. Stryer L, J. Mol. Biol., 13, 482 (1965)
  43. Hawe A, Sutter M, Jiskoot W, Pharm. Res. Dordr., 25, 1487 (2008)
  44. Sharma VK, Kalonia DS, Pharm. Res. Dordr., 20, 1721 (2003)
  45. Fujita K, MacFarlane DR, Forsyth M, Chem. Commun., 4804 (2005).